3-aminoalkyl-2-aryl-indole derivatives and their use as GnRH antagonists

ABSTRACT

The present invention relates to compounds of formula I which are antagonists of gonadotropin releasing hormone (GnRH) activity. The invention also relates to pharmaceutical formulations, the use of a compound of the present invention in the manufacture of a medicament, a method of therapeutic treatment using such a compound and processes for producing the compounds

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB02/02116, filed May 8, 2002, whichclaims priority from Sweden Application No. 0101692-2, filed May 14,2001, the specification of which is incorporated by reference herein.International Application No. PCT/GB02/02116 was published under PCTArticle 21(2) in English.

FIELD OF THE INVENTION

The present invention relates to compounds which are antagonists ofgonadotropin releasing hormone (GnRH) activity. The invention alsorelates to pharmaceutical formulations, the use of a compound of thepresent invention in the manufacture of a medicament, a method oftherapeutic treatment using such a compound and processes for producingthe compounds.

BACKGROUND OF INVENTION

Gonadotropin releasing hormone (GnRH) is a decapeptide that is secretedby the hypothalamus into the hypophyseal portal circulation in responseto neural and/or chemical stimuli, causing the biosynthesis and releaseof luteinizing hormone (LH) and follicle-stimulating hormone (FSH) bythe pituitary. GnRH is also known by other names, includinggonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSHRH) and LH/FSH releasing factor (LH/FSH RF).

GnRH plays an important role in regulating the action of LH and FSH (byregulation of their levels), and thus has a role in regulating thelevels of gonadal steroids in both sexes, including the sex hormonesprogesterone, oestrogens and androgens. More discussion of GnRH can befound in WO 98/5519 and WO 97/14697, the disclosures of which areincorporated herein by reference.

It is believed that several diseases would benefit from the regulationof GnRH activity, in particular by antagonising such activity. Theseinclude sex hormone related conditions such as sex hormone dependentcancer, benign prostatic hypertrophy and myoma of the uterus. Examplesof sex hormone dependent cancers are prostatic cancer, uterine cancer,breast cancer and pituitary gonadotrophe adenoma.

The following disclose compounds purported to act as GnRH antagonists:WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 55116, WO98/55119, WO 98/55123, WO 98/55470, WO 98/55479, WO 99/21553, WO99/21557, WO 99/41251, WO 99/41252, WO 00/04013, WO 00/69433, WO99/51231, WO 99/51232, WO 99/51233, WO 99/51234, WO 99/51595, WO99/51596, WO 00/53178, WO 00/53180, WO 00/53179, WO 00/53181, WO00/53185 and WO 00/53602.

It would be desirable to provide further compounds, such compounds beingGnRH antagonists.

SUMMARY OF THE INVENTION

The present invention accordingly provides a compound of formula I or asalt, pro-drug or solvate thereof

whereinfor A, either:—

-   (i) A represents hydrogen or optionally-substituted C₁ to C₈ alkyl;    or-   (ii) the structure N—A(—R⁴) represents an optionally-substituted 3-    to 8-membered heterocyclic ring optionally containing from 1 to 3    further heteroatoms independently selected from O, N and S;-   B represents a direct bond or optionally substituted C₁ to C₅    alkylene;-   C represents a mono- or bi-cyclic aromatic ring structure optionally    having at least one substituent selected from CN, NR⁵R⁶, an    optionally substituted C₁ to C₈ alkyl, optionally substituted C₁ to    C₈ alkoxy or halo;-   D represents hydrogen; optionally substituted C₁ to C₈ alkyl; or    (CH₂)_(b)—R^(a), wherein R^(a) represents C₃ to C₈ cycloalkyl and b    is zero or an integer from 1 to 6;-   E is selected from an optionally substituted 3- to 8-membered    heterocyclic ring containing from 1 to 4 heteroatoms independently    selected from O, N and S; or a group of formula II; III; IV; V; VI;    VII or VIII

-   -   wherein het represents an optionally substituted 3- to        8-membered heterocyclic ring containing from 1 to 4 heteroatoms        independently selected from O, N and S;        for X and Y, either:—

-   (iii) X represents N and Y represents CN; hydrogen or —CONR^(b)R^(c)    where R^(b) and R^(c) are independently selected from hydrogen and    C₁ to C₈ alkyl;

-   (iiia) X represents CH and Y represents NO₂; or

-   (iv) X—Y represents O;    for R¹ and R², either:—

-   (v) R¹ and R² are independently selected from hydrogen and    optionally substituted C₁ to C₈ alkyl; or

-   (vi) R¹ and R² together represent carbonyl; or

-   (vii)

represents an optionally substituted 3- to 8-membered heterocyclic ringcontaining from 1 to 3 further heteroatoms independently selected fromO, N and S, and R² meets the definition in option (v);

-   R³ meets the definition in option (vii) or represents hydrogen or    optionally substituted C₁ to C₈ alkyl;-   R⁴ meets the definition in option (ii) or when A meets the    definition in option (i) R⁴ represents hydrogen or optionally    substituted C₁ to C₈ alkyl;-   R⁵ and R⁶ are independently selected from hydrogen; optionally    substituted C₁ to C₈ alkyl and optionally substituted aryl;    for R⁷ and R^(7a), either:—-   (viii) R⁷ and R^(7a) are independently selected from hydrogen or    optionally substituted C₁ to C₈ alkyl; or-   (ix)

represents an optionally substituted 3 to 7-membered cycloalkyl ring;For R⁸ and R⁹, either:—

-   (x) R⁸ is selected from hydrogen; optionally substituted C₁ to C₈    alkyl; optionally substituted aryl; —R^(d)—Ar, where R^(d)    represents C₁ to C₈ alkylene and Ar represents optionally    substituted aryl; and optionally substituted 3- to 8-membered    heterocyclic ring optionally containing from 1 to 3 further    heteroatoms independently selected from O, N and S; and    -   R⁹ is selected from hydrogen; optionally substituted C₁ to C₈        alkyl and optionally substituted aryl;-   (xi) wherein E represents a group of formula II or III, then the    group NR⁸(—R⁹) represents an optionally substituted 3- to 8-membered    heterocyclic ring optionally containing from 1 to 3 further    heteroatoms independently selected from O, N and S; or-   (xii) wherein E represents structure VI,

represents an optionally substituted 3- to 8-membered heterocyclic ringoptionally containing from 1 to 4 heteroatoms independently selectedfrom O, N and S;with the proviso that:when A is C₁ to C₈ alkyl or the structure N—A(—R⁴) represents anoptionally-substituted 3- to 8-membered heterocyclic ring containingfrom 1 to 3 heteroatoms independently selected from O, N and S; Xrepresents N and Y represents CN or hydrogen, X represents CH and Yrepresents NO₂ or X—Y represents O; then the optional substituents on Aare not selected from optionally substituted phenyl or anoptionally-substituted 3- to 8-membered heterocyclic ring.

The present invention also provides a pharmaceutical formulationcomprising such a compound, or salt, pro-drug or solvate thereof, and apharmaceutically acceptable diluent or carrier.

Furthermore, the present invention provides the following uses of thecompound, or salt, pro-drug or solvate thereof:—

-   (a) use in the manufacture of a medicament for antagonising    gonadotropin releasing hormone activity;-   (b) use in the manufacture of a medicament for administration to a    patient, for reducing the secretion of luteinizing hormone by the    pituitary gland of the patient; and-   (c) use in the manufacture of a medicament for administration to a    patient, for therapeutically treating and/or preventing a sex    hormone related condition in the patient.

The present invention also relates to a method of antagonisinggonadotropin releasing hormone activity in a patient, comprisingadministering the compound, or salt, pro-drug or solvate thereof, to thepatient.

In addition, the invention provides a process of producing the compound,or salt, pro-drug or solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

As discussed above, the present invention provides a compound of formulaI or a salt, pro-drug or solvate thereof

whereinfor A, either:—

-   (i) A represents hydrogen or optionally-substituted C₁ to C₈ alkyl    (preferably, C₁ to C₄ alkyl, for example methyl or ethyl); or-   (ii) the structure N—A(—R⁴) represents a optionally-substituted 3-    to 8-membered heterocyclic ring (preferably, a 5- or 6-membered    monocyclic ring) optionally containing from 1 to 3 (eg, 1) further    heteroatoms independently selected from O, N and S.    When the structure N—A(—R⁴) represents a 3- to 8-membered    heterocyclic ring, the heterocyclic ring is preferably selected from    an optionally-substituted group of formula, IX, X and XI:

Further preferably when the structure N—A(—R⁴) represents a 3- to8-membered heterocyclic ring, the heterocyclic ring is selected from agroup of formula XII or XIII:

-   -   wherein R¹² represents C₁ to C₈ alkyl; —(CH₂)_(c)NR^(e)R^(f),        where c is zero or an integer from 1 to 4, and R^(e) and R^(f)        independently represent hydrogen or C₁ to C₈ alkyl; hydroxy;        halo; CN; C₁ to C₈ alkoxy; or CF₃.

-   B represents a direct bond or optionally substituted C₁ to C₅    alkylene (preferably, C₁ to C₄ alkylene, for example methylene or    ethylene).

-   C represents a mono- or bi-cyclic aromatic ring structure    (preferably, phenyl) optionally having at least one substituent (eg,    1, 2 or 3 substituents) selected from CN, NR⁵R⁶, an optionally    substituted C₁ to C₈ alkyl (preferably, C₁ to C₄ alkyl, eg, methyl    or ethyl), optionally substituted C₁ to C₈ alkoxy (preferably, C₁ to    C₆ alkoxy, eg, methoxy, ethoxy or tert-butoxy) or halo (eg, F, Br or    Cl).    Preferably, C represents

-   -   wherein Me represents methyl.

-   D represents hydrogen; optionally substituted C₁ to C₈ alkyl    (preferably, C₁ to C₆ alkyl, eg, methyl, ethyl or tert-butyl); or    (CH₂)_(b)—R^(a), wherein R^(a) represents C₃ to C₈ cycloalkyl (eg,    C₃, C₄, C₅ or C₆ cycloalkyl) and b is zero or an integer from 1 to    6.

-   E is selected from an optionally substituted 3- to 8-membered    heterocyclic ring (preferably, a 5- or 6-membered monocyclic ring)    containing from 1 to 4 (eg, 1 or 2) heteroatoms independently    selected from O, N and S; or a group of formula II; III; IV; V; VI;    VII or VIII

-   -   wherein het represents an optionally substituted 3- to        8-membered heterocyclic ring (preferably, a 5- or 6-membered        monocyclic ring) containing from 1 to 4 (eg, 1 or 2) heteroatoms        independently selected from O, N and S.        Preferably, E represents    -   (a) structure II of the sub-formula

-   -   -   wherein Me represents methyl;

    -   (b) structure II, wherein

represents cyclopropyl or cyclobutyl; or

-   -   (c) structure VIII wherein R⁷ and R^(7a) each represent methyl.        For X and Y, either:—

-   (iii) X represents N and Y represents CN; hydrogen or —CONR^(b)R^(c)    where R^(b) and R^(c) are independently selected from hydrogen and    C₁ to C₈ alkyl;

-   (iiia) X represents CH and Y represents NO₂; or

-   (iv) X—Y represents O.    Preferably X and Y represent either:—

-   (a) X represents CH and Y represents NO₂;

-   (b) X represents N and Y represents CN; or

-   (c) X represents N and Y represents hydrogen.    Further preferably X and Y represent either:—    -   (a) X represents CH and Y represents NO₂; or    -   (b) X represents N and Y represents CN;        In a further embodiment of the invention X represents N and Y        represents —CONR^(b)R^(c) wherein R^(b) and R^(c) are as defined        above.

For R¹ and R² either:—

-   -   (v) R¹ and R² are independently selected from hydrogen and        optionally substituted C₁ to C₈ alkyl (preferably, C₁ to C₆        alkyl, eg, methyl, ethyl or tert-butyl); or

-   (vi) R¹ and R² together represent carbonyl; or

-   (vii)

represents an optionally substituted 3- to 8-membered heterocyclic ring(preferably, a 5- or 6-membered monocyclic ring) containing from 1 to 3(eg, 1 or 2) further heteroatoms independently selected from O, N and S,and R² meets the definition in option (v).In one embodiment, R¹ and R² each represent hydrogen and B represents C₁alkylene.

-   In a further embodiment of the invention R¹ represents H, R²    represents methyl and B represents C₁ alkylene.-   R³ meets the definition in option (vii) or represents hydrogen or    optionally substituted C₁ to C₈ alkyl (preferably, C₁ to C₆ alkyl,    eg, methyl, ethyl or tert-butyl).-   R⁴ meets the definition in option (ii) or when A meets the    definition in option (i) R⁴ represents hydrogen or optionally    substituted C₁ to C₈ alkyl (preferably, C₁ to C₆ alkyl, eg, methyl,    ethyl or tert-butyl).-   R⁵ and R⁶ are independently selected from hydrogen; optionally    substituted C₁ to C₈ alkyl (preferably, C₁ to C₆ alkyl, eg, methyl,    ethyl or tert-butyl); and optionally substituted aryl (eg, phenyl).    For R⁷ and R^(7a), either:—-   (viii) R⁷ and R^(7a) are independently selected from hydrogen or    optionally substituted C₁ to C₈ alkyl (preferably, C₁ to C₆ alkyl,    eg, methyl, ethyl or tert-butyl; in one embodiment R⁷ and R^(7a) are    both methyl); or-   (ix)

represents an optionally substituted 3 to 7-membered (eg, 3-, 4-, 5- or6-membered) cycloalkyl ring;For R⁸ and R⁹, either:—

-   (x) R⁸ is selected from hydrogen; optionally substituted C₁ to C₈    alkyl (preferably, C₁ to C₆ alkyl, eg, methyl, ethyl or tert-butyl;    in one embodiment both R⁸ and R⁹ are ethyl); optionally substituted    aryl (eg, optionally substituted phenyl); —R^(d)—Ar, where R^(d)    represents C₁ to C₈ alkylene (preferably, C₁ to C₆ alkylene, eg,    methylene or ethylene) and Ar represents optionally substituted aryl    (eg, optionally substituted phenyl); and an optionally substituted    3- to 8-membered heterocyclic ring (preferably, a 5- or 6-membered    monocyclic ring) containing from 1 to 3 (eg, 1 or 2) further    heteroatoms independently selected from O, N and S; and    -   R⁹ is selected from hydrogen; optionally substituted C₁ to C₈        alkyl (preferably, C₁ to C₆ alkyl, eg, methyl, ethyl or        tert-butyl) and optionally substituted aryl (eg, optionally        substituted phenyl); or-   (xi) wherein E represents a group of formula II or III, then the    group NR⁸(—R⁹) represents an optionally substituted 3- to 8-membered    heterocyclic ring (preferably, a 5- or 6-membered monocyclic ring)    containing from 1 to 3 (eg, 1 or 2) further heteroatoms    independently selected from O, N and S; or-   (xii) wherein E represents structure VI,

represents an optionally substituted 3- to 8-membered heterocyclic ring(preferably, a 5- or 6-membered monocyclic ring) containing from 1 to 4(eg, 1 or 2) heteroatoms independently selected from O, N and S;with the proviso that:when A is C₁ to C₈ alkyl or the structure N—A(—R⁴) represents anoptionally-substituted 3- to 8-membered heterocyclic ring containingfrom 1 to 3 heteroatoms independently selected from O, N and S; Xrepresents N and Y represents CN or hydrogen, X represents CH and Yrepresents NO₂ or X—Y represents O; then the optional substituents on Aare not selected from optionally substituted phenyl or anoptionally-substituted 3- to 8-membered heterocyclic ring.

Whilst pharmaceutically-acceptable salts of compounds of the inventionare preferred, other non-pharmaceutically-acceptable salts of compoundsof the invention may also be useful, for example in the preparation ofpharmaceutically-acceptable salts of compounds of the invention.

In the present specification, unless otherwise indicated, an alkyl,alkylene or alkenyl moiety may be linear or branched.

The term “alkylene” refers to the group —CH₂—. Thus, C₈ alkylene forexample is —(CH₂)₈—.

The term “aryl” refers to phenyl or naphthyl.

The term “carbamoyl” refers to the group —CONH₂.

The term “halo” refers to fluoro, chloro, bromo or iodo.

The term “heterocyclic ring” refers to a 5-10 membered aromatic mono orbicyclic ring or a 5-10 membered saturated or partially saturated monoor bicyclic ring, said aromatic, saturated or partially unsaturatedrings containing up to 5 heteroatoms independently selected fromnitrogen, oxygen or sulphur, linked via ring carbon atoms or ringnitrogen atoms where a bond from a nitrogen is allowed, for example nobond is possible to the nitrogen of a pyridine ring, but a bond ispossible through the 1-nitrogen of a pyrazole ring. Examples of 5- or6-membered aromatic heterocyclic rings include pyrrolyl, furanyl,imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl,isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl andthienyl. A 9 or 10 membered bicyclic aromatic heterocyclic ring is anaromatic bicyclic ring system comprising a 6-membered ring fused toeither a 5 membered ring or another 6 membered ring. Examples of 5/6 and6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl,benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl,quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl,cinnolinyl and naphthyridinyl. Examples of saturated or partiallysaturated heterocyclic rings include pyrrolinyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl anddihydropyrimidinyl.

The term “aromatic ring” refers to a 5-10 membered aromatic mono orbicyclic ring optionally containing up to 5 heteroatoms independentlyselected from nitrogen, oxygen or sulphur. Examples of such “aromaticrings” include: phenyl, pyrrolyl, furanyl, imidazolyl, triazolyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl,1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. Preferredaromatic rings include 'phenyl, thienyl and pyridyl.

The symbol

denotes where the respective group is linked to the remainder of themolecule.

Where optional substitution is mentioned at various places, this refersto one, two, three or more optional substituents. Unless otherwiseindicated above (ie, where a list of optional substituents is provided),each substituent can be independently selected from C₁ to C₈ alkyl (eg,C₂ to C₆ alkyl, and most preferably methyl, ethyl or tert-butyl); C₃ toC₈ cycloalkoxy, preferably cyclopropoxy, cyclobutoxy or cyclopentoxy; C₁to C₆ alkoxy, preferably methoxy or C₂ to C₄ alkoxy; halo, preferably Clor F; Hal₃C—, Hal₂CH—, HalCH₂—, Hal₃CO—, Hal₂CHO or Hal CH₂O, whereinHal represents halo (preferably F); R^(g)CH₂O—, R^(h)C(O)N(R)—,R^(h)SO₂N(R)— or R^(g)—R^(h)N—, wherein R^(g) and R^(h) independentlyrepresent hydrogen or C₁ to C₈ alkyl (preferably methyl or C₂ to C₆alkyl or C₂ to C₄ alkyl), or R^(g)—R^(h)N— represents an optionallysubstituted C₃ to C₈, preferably C₃ to C₆, heterocyclic ring optionallycontaining from 1 to 3 further heteroatoms independently selected fromO, N and S; hydrogen; or R^(k)C(O)O— or R^(k)C(O)—, R^(k) representinghydrogen, optionally substituted phenyl or C₁ to C₆ alkyl (preferablymethyl, ethyl, iso-propyl or tert-butyl). For optional substitution ofthe heterocyclic ring represented by R^(g)—R^(h)N—, at least one (eg,one, two or three) substituents may be provided independently selectedfrom C₁ to C₆ alkyl (eg, C₂ to C₄ alkyl, more preferably methyl);phenyl; CF₃O—; F₂CHO—; C₁ to C₈ alkoxy, preferably methoxy, ethoxy or C₃to C₆ alkoxy; C₁ to C₈ alkoxyC(O), preferably methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl or C₃ to C₆ alkoxyC(O)—;phenoxycarbonyl; phenoxy; C₁ to C₈ alkanoyl, preferably acetyl, ethanoylor C₃ to C₆ alkyanoyl; carboxy; C₁ to C₈ alkylS(O)_(nn) wherein nn is aninteger between 0 and 2, preferably methylthio, ethylthio, C₃ to C₆alkylthio, methylsulphinyl, ethylsulphinyl, C₃ to C₆ alkylsulphinyl,methylsulphonyl, ethylsulphonyl or C₃ to C₆ alkylsulphonyl; hydroxy;halo (eg, F, Cl or Br); R^(m)R^(n)N— where R^(m) and R^(n) areindependently hydrogen or C₁ to C₆ alkyl (preferably C₂ to C₄ alkyl,more preferably methyl, most preferably R^(m)=R^(n)=methyl); and nitro.

Where optional substitution of a ring is mentioned at various places,this most preferably refers to one, two, three or more substituentsselected from C₁ to C₈ alkyl (eg, C₂ to C₆ alkyl, and most preferablymethyl); C₁ to C₈ alkoxy, preferably methoxy, ethoxy or C₃ to C₆ alkoxy;C₁ to C₈ alkylS(O)_(nn) wherein nn is an integer between 0 and 2,preferably methylthio, ethylthio, C₃ to C₆ alkylthio, methylsulphinyl,ethylsulphinyl, C₃ to C₆ alkylsulphinyl, methylsulphonyl, ethylsulphonylor C₃ to C₆ alkylsulphonyl; halo (eg, F, Cl or Br); CN; and NO₂.

Preferred optional substituents on A when A is C₁ to C₈ alkyl include:optionally-substituted phenyl or an optionally substituted 3- to8-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from O, N and S.

Preferred optional substituents when the structure N—A(—R⁴) represents a3- to 8-membered heterocyclic ring include: C₁ to C₄ alkyl, N-(C₁ to C₄alkyl)amino, N,N-di-(C₁ to C₄ alkyl)amino, CN, halo, carbamoyl,NHC(O)—R^(p), C(O)NH—R^(p), NHS(O)_(nn)R^(p), C₁ to C₄ alkylS(O)_(nn);wherein nn and mm independently represent an integer between 0 and 2.and R^(p) is C₁ to C₄ alkyl.

Preferred optional substituents on A when the optional substituents is a3- to 8-membered heterocyclic ring include optionally substitutedpyridyl, thienyl, piperidinyl, imidazolyl, triazolyl, thiazolyl,pyrrolidinyl, piperazinyl, morpholinyl or imidazolinyl. Furtherpreferred optional substituents include pyridyl, or a group of formulaXIV, XV, XVI, XVII, XVIII, XIX or XX:

wherein

-   R¹¹ represents hydrogen; optionally substituted C₁ to C₈ alkyl    (preferably, C₁ to C₆ alkyl, eg, methyl, ethyl or tert-butyl);    hydroxy; halo (eg, F, Cl or Br); CN; C₁ to C₈ alkoxy (preferably, C₁    to C₆ alkoxy, eg, methoxy or ethoxy); or CF₃; and-   R^(11′) represents hydrogen or optionally substituted C₁ to C₈ alkyl    (preferably, C₁ to C₆ alkyl, eg, methyl).

A preferred group of compounds of the invention comprises a compound offormula Ia:

wherein:

-   E is selected from a II, III or VIII:

and A, B, D, X, Y, R¹, R², R³, R⁴, R⁷, R^(7a), R⁸ and R⁹ are as definedabove; or a salt, pro-drug or solvate thereof.

A further preferred group of compounds of the invention comprises acompound of formula Ib:

wherein:E is selected from a group of formula II, III or VIII:

and A, B, D, X, Y, R³, R⁴, R⁷, R^(7a), R¹ and R⁹ are as defined above;or a salt, pro-drug or solvate thereof.

A yet further preferred group of compounds of the invention comprises acompound of formula Ia or Ib wherein:

E is a group of formula II:

NR⁸(—R⁹) represents an optionally substituted 7- to 8-membered bicyclicheterocyclic ring and A, B, D, X, Y, R³, R⁴, R⁷, R^(7a), R⁸ and R⁹ areas defined above; or a salt, pro-drug or solvate thereof.

Particularly preferred compounds according to the present invention arewherein the compound is selected from a compound of formula XXI toXXXI:—

It is to be understood that, insofar as certain of the compounds of theinvention may exist in optically active or racemic forms by virtue ofone or more asymmetric carbon atoms, the invention includes in itsdefinition any such optically active or racemic form which possesses theproperty of antagonizing gonadotropin releasing hormone (GnRH) activity.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, activity of these compounds may be evaluatedusing the standard laboratory techniques referred to hereinafter.

The invention also relates to any and all tautomeric forms of thecompounds of the different features of the invention that possess theproperty of antagonizing gonadotropin releasing hormone (GnRH) activity.

It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It is to be understood that the present inventionencompasses all such solvated forms which possess the property ofantagonizing gonadotropin releasing hormone (GnRH) activity.

The compounds of Formula I may be administered in the form of a pro-drugwhich is broken down in the human or animal body to give a compound ofthe Formula I. Examples of pro-drugs include in-vivo hydrolysable estersof a compound of the Formula I. Various forms of pro-drugs are known inthe art. For examples of such pro-drug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the Formula I containinga carboxy or a hydroxy group is, for example, apharmaceutically-acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically-acceptable esters for carboxy include C₁ toC₆alkoxymethyl esters for example methoxymethyl, C₁ to₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, C₃ to C₈cycloalkoxycarbonyloxy C₁ to C₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample 5-methyl-1,3-dioxolen-2-onylmethyl; and C₁ toC₆alkoxycarbonyloxyethyl esters.

An in-vivo hydrolysable ester of a compound of the Formula I containinga hydroxy group includes inorganic esters such as phosphate esters(including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers andrelated compounds which as a result of the in-vivo hydrolysis of theester breakdown to give the parent hydroxy group/s. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

The compounds of formula I can be prepared by a process comprising astep selected from (a) to (e) as follows, these processes are providedas a further feature of the invention:—

(a) Reaction of a compound of formula XXXII as follows

(b) Cleavage of the CN group of compound of formula XXXIII in thepresence of acid to produce compound of formula XXXIV

(c) Reaction of compound of formula XXXV as follows

(d) Reaction of compound of formula XXXVII as follows

(e) Reaction of compound of formula XXXIX as follows

and thereafter if necessary:i) converting a compound of the formula I into another compound of theformula I;ii) removing any protecting groups;iii) forming a salt, pro-drug or solvate.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula I may involve, at an appropriate stage, theaddition and subsequent removal of one or more protecting groups.

The protection and de-protection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thede-protection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or alkoxycarbonyl group or an aroyl group maybe removed for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thede-protection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

EXPERIMENTAL

General Reaction Schemes

In the following schemes wherein Ri, Rii and Riii represent optionalsubstituents on the phenyl ring which are optionally protected asnecessary and R represents a protecting group, group C has been depictedas substituted phenyl for illustration purposes only. Other definitionsof C are also appropriate.

Tryptamines, such as 3 can be synthesised by the classic Fisher indolesynthesis reaction by the condensation of a hydrazine 1 and a ketone 2,bearing hydrogen atoms α to the carbonyl (Scheme a). Treatment of thesereactants in a suitable solvent, such as acetic acid, ethanol,tert-butanol, toluene, in the presence of an acid, such as sulphuric,hydrochloric, polyphosphoric and/or a Lewis acid, for example, borontrifluoride, zinc chloride, magnesium bromide, at elevated temperatures(for example 100° C.), gives the desired product. R represents aprotecting group, eg tert-butylcarbamate or phthalimide.

Tryptamines, such as represented in structure 5, can also be made usingaldehydes 4, bearing hydrogen atoms α to the carbonyl, by cyclizationusing the conditions above. In this case the substituent at the2-position must be added later (see scheme d).

Tryptamine may also be synthesised utilising the Granburg reaction,wherein a hyradazine 1 is mixed with ketone 6, bearing a chlorine atom γto the carbonyl, and heated in a suitable solvent such as ethanol,tert-butanol, toluene at a temperature between 50° C. and 120° C.(Scheme c).

The tryptamine 5 can be treated with a ‘bromine source’, such asmolecular bromide, pyridinium tribromide, pyrrolidone hydrobromide orpolymer supported reagent equivalents, in an inert solvent such aschloroform, methylene chloride at −10° C. to 25° C. to yield the 2-bromocompound 8 (Scheme d). Reaction under Suzuki conditions with apalladium(0) catalyst, a weak base such aqueous sodium carbonate orsaturated sodium hydrogen carbonate and the like, and a substituted arylboronic acid from commercial sources or prepared (as described in:Gronowitz, S.; Homfeldt, A. -B.; Yang, Y., -H Chem. Sci. 1986, 26,311-314), in an inert solvent such as toluene, benzene, dioxane, THF,DMF and the like, with heating between 25° C. and 100° C., preferably80° C., for a period of 1-12 hours, to give the desired compound 3.

The hydrazines 1 can be purchased from commercial sources either as afree base or suitable salt (e.g. hydrochloride), which are bothacceptable under the reaction conditions. Hydrazines may be synthesisedby the two-step process of diazotisation of an aniline, under thepreferred conditions of concentrated hydrochloric acid sodium nitrite ata temperature between −10° C. and −5° C., then reduction under thepreferred conditions of tin(II) chloride in concentrated hydrochloricacid at a temperature between −10° C. and −5° C.

Substituted ketones 2 can be prepared, as outlined in Scheme e startingfrom appropriate acid chlorides such as 9. Treatment of the acidchloride with N,N-dimethylhydroxylamine hydrochloride in the presence ofan amine base such as triethylamine, and a suitable solvent such asmethylene chloride at a temperature of −10° C. to 25° C., yields theamide 10. Further reaction with a substituted aryl organolithium(prepared essentially as described in Wakefield B, J.; OrganolithiumMethods Academic Press Limited, 1988, pp. 27-29 and references therein)in an inert solvent such as tetrahydrofuran, diethyl ether, benzene,toluene or mixture thereof and the like, at a temperature between −100°C. and 0° C. then quenching of the reaction mixture with a mineral acidsuch as hydrochloric acid, yields the aryl ketone 2.

Commencing with a readily available amino acid with a suitable chainlength [a] 11, the nitrogen atom can be brought in at the beginning ofthe synthesis by the route shown in Scheme f. Protection of the aminegroup of 11 with a tert-butylcarbamate group is achieved by condensationwith di-tert-butyl di-carbonate in the presence of an amine base, forexample triethylamine, in an inert solvent such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran and mixtures thereof andthe like, at a temperature of −10° C. to 25° C. Coupling of the acidproduct with N,N-dimethylhydroxylamine in the presence of a couplingreagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC) or 1,3-dicyclohexylcarbodiimide (DCC) or the like, with or without1-hydroxybenotriazole (HOBt), and suitable amine base, such astriethylamine and the like, in an inert solvent such as methylenechloride, chloroform, dimethylformamide, or mixture thereof, at or nearroom temperature for a period of 3 to 24 hours provided thecorresponding coupled product 12. Following the same route describedabove for scheme d, the aryl group can then be installed.

Scheme g illustrates another method for the synthesis of ketone such as2 and 16, where the nitrogen group is introduced at a latter stage. Asabove a Weinreb amide 14 can be synthesised from an acid chloride.Treatment with the required amine, in an inert solvent such as THF,toluene, water and the such like can displace the group X to give 17. Asabove the aryl group can be introduced by displacement of the Weinrebamide with a suitable aryl lithium nucleophile. Alternatively thenitrogen atom can be introduced already protected as a phthalimide bydisplacement of the group x by potassium phthalimide, or similar saltthereof, by heating in an inert polar solvent such as DMF, DMSO, THF,toluene with or without the presence of a catalyst such astetrabutylammonium iodide and the such like, to yield the compound 15.Again displacement of the Weinreb amide with an organolithium speciescompletes the synthesis of a ketone suitable for cyclization under theFischer condition described above for indole synthesis.

An alternative approach to a phthalimide protected nitrogen ketone, suchas 16, can be taken by firstly treating a lactone, with an organolithiumspecies as in the above schemes in a suitable solvent such as THF orether at a low temperature of between −100° C. and −50° C. to yield aprimary alcohol 18 (Scheme h). The hydroxyl function of 18 is replacedwith a phthalimide group by a Mitsunobu reaction with an activatingagent such as diethyldiazocarboxylate (DEAD),diisopropyldiazocarboxylate or the like with triphenylphosphine,tri-butylphosphine and the like, in an inert solvent such as benzene,toluene, tetrahydrofuran or mixtures thereof to give the desired ketone16.

If the group D was not present on the starting hydrazine beforecyclization to form an indole it may be added post cyclization by analkylation reaction (19→3). The indole is de-protonated by a strongbase, such as sodium hydride, n-butyl lithium, lithium diisopropylamine,sodium hydroxide, potassium tert-butoxide in a suitable inert solventsuch as THF, DMF, DMSO and the such like, and an alkyl halide added andthe mixture stirred at room temperature.

Depending on the route used above a tryptamine 20 suitable forconversion to a cyano-guandine can be formed by removal of theprotecting group, for example if a tert-butylcarbamate group was usedthen removal is accomplished using a strong acid, for exampletrifluoroacetic acid or hydrochloric acid in an inert solvent such asmethylene chloride, chloroform, THF or dioxane at a temperature between−20° C. and 25° C. A phthalimide group, for example, can be removed byhydrazine in a suitable solvent for example methanol, ethanol, methylenechloride, chloroform, THF dioxane at a temperature between −20° C. and25° C. The primary amine 20 can be converted to a cyano-guanidine 22 bythe two step process of reaction with diphenyl cyanocarbonimidate in aninert organic solvent such as iso-propyl alcohol, methylene chloride,chloroform, benzene, tetrahydrofuran and the like, at a temperaturebetween −20° C. and 50° C., followed by condensation with anappropriately substituted amine in an inert organic from the list above,with heating at a temperature between −20° C. and 100° C. (Scheme I20→21→22). Further treatment of 22 with 2 molar Hydrochloric acid inmethanol at elevated temperature yields guanidine compounds 23.

Similarly, reaction with 1,1′-bis(methylthio)-2-nitroethylene in aninert solvent such methylene chloride, chloroform, benzene,tetrahydrofuran and the like, followed by condensation with anappropriately substituted amine in an inert organic solvent from thelist above yields the nitroethyleneimidazo[1,2-a]pyridine 25 (Scheme j,20→24→25).

Again in a similar fashion the suitable tryptamine 20, derived fromde-protection, can be converted to a urea by either direct treatmentwith an iso-cyanate in an inert solvent such as methylene chloride,chloroform or THF and the such like, or by a two step procedure ofreaction with triphosgene (20→27) followed by addition of an amine(27→26), bearing the required substitution to yield 26.

EXAMPLES

The invention will now be illustrated with the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at room temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon ornitrogen;

(iii) yields are given for illustration only and are not necessarily themaximum attainable;

(iv) the structures of the end-products of the Formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(vi) chromatography was performed on silica (Merck Keiselgel: Art.9385);

(vii) isolute™ refers to silica (SiO₂) based columns with irregularparticles with an average size of 50 μm with nominal 60 Å porosity[Source: Jones Chromatography, Ltd., Glamorgan, Wales, United Kingdom].

Abbreviations

brine a saturated solution of sodium chloride in distilled water DCC1,3-dicyclohexylcarbodiimide DEAD diethyldiazocarboxylate DMSO Dimethylsulphoxide DMF dimethylformamide EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt1-hydroxybenotriazole IPA isopropyl alcohol RM reaction mixture RT roomtemperature THF tetrahydrofuran

Example 1

STRUCTURE EXAMPLE

1.01Synthesis of this compound is described with reference to Scheme 1below.Morpholine (260 mg, 3 mmol) was added to a stirred suspension of L (0.18mmol) in IPA (2 ml) and the mixture heated at reflux for 36 hours. TheRM was concentrated in vacuo and the residues purified by chromatographyon SiO₂ eluting with 5% MeOH/CH₂Cl₂ to give 1.01 as an off-white foamwhite 43.5 mg (46%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.00-1.20 (m,3H); 1.60 (s,6H);2.4 (s,6H); 2.80-3.00 (m,2H); 3.08-3.14 (m,4H); 3.2-3.3 (t,2H); 3.3-3.42(m, 2H); 3.5-3.58 (m,4H); 3.62-3.72 (m,2H); 4.5-4.6 (m,1H); 7.03 (s,1H);7.05-7.13 (m,1H); 7.20 (s,2H); 7.2-7.36 (m,1H); 7.42 (s,1H); 8.15(s,1H).

MS (ES⁺) m/z (M+H)⁺ 543.39

MS (ES⁻) m/z (M−H)⁻ 541.33

Following a procedure similar to that described in Example 1, thefollowing compounds were prepared.

STRUCTURE EXAMPLE MS (ES)+

1.02 556.74 (M + H)+

1.03 585.55 (M + H)+

1.04 542.54 (M + H)+

1.05 570.51 (M + H)+

1.06 527.48 (M + H)+

1.07 473.48 (M + H)+

Example 2

EXAM- STRUCTURE PLE

2Synthesis of this compound is described with reference to Scheme 2below.Methylamine (1 ml, 2.00 mmol) was added to a stirred suspension of M(46.4 mg, 0.089 mmol) in CH₂Cl₂ (2 ml) and the mixture stirred for 60hrs. The RM was concentrated in vacuo and the residues purified bychromatography on SiO₂ (Isolute, 10 g), eluting with a gradient 0-10%MeOH/CH₂Cl₂ to give 2.01 as a white solid 31.3 mg (70%).

¹H NMR (300 MHz, CDCl₃) 0.6-0.8 (m,3H); 1.0-1.2 (m,3H); 1.6 (s,6H); 2.35(s,6H); 2.40-2.60 (m,3H); 2.8-3.0 (m,2H); 3.00-3.60 (m, 6H); 4.4-4.9(m,1H); 6.2-6.6 (m,1H); 7.02 (s,1H); 7.1 (d,1H); 7.15 (bs,2H); 7.3-7.45(m,2H); 8.45 (s,1H); 9.80-10.2 (bm,1H).

MS (ES⁺) m/z (M+H)⁺ 506.63

MS (ES⁻) m/z (M−H)⁻ 504.64

Example 3

STRUCTURE EXAMPLE

3Synthesis of this compound is described with reference to Scheme 3below.A solution of K (100 mg, 0.25 mmol) in MeOH (5 mL) was treated with 2NHCl (2 mL) followed Potassium cyanate (405 mg, 5 mmol). The mixture wasstirred for 18 hrs then quenched with saturated NaHCO₃ (aq) (100 mL) andextracted with EtOAc (3×50 mL). The combined organics were washed withbrine (2×50 mL), dried over MgSO₄, filtered and evaporated. The crudeswere purified by chromatography on SiO₂ eluting with a gradient 0-5%MeOH/CH₂Cl₂ to give 3 as an off-white foam 82.0 mg (73%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.00-1.20 (m,3H); 1.60 (s,6H);2.18 (s,6H); 2.84-3.00 (m,2H); 3.06-4.00 (m, 6H); 4.24 (s,2H); 4.66-4.72(m,1H); 7.00-7.1 (m,2H); 7.2 (s,2H); 7.3-7.34 (m,1H); 7.46 (s,1H); 8.12(s,1H).

MS (ES⁺) m/z (M+H)⁺ 449.57

MS (ES⁻) m/z (M−H)⁻ 447.59

Example 4

STRUCTURE EXAMPLE

4Synthesis of this compound is described with reference to Scheme 4below.3-(Methylsulphonyl) pyrrolidine (746 mg, 5 mmol) was added to a stirredsuspension of Q (547 mg, 1 mmol) in IPA (10 mL) and the mixture heatedat reflux for 18 hrs. The RM was concentrated in vacuo and the residuespurified by chromatography on SiO₂ (Isolute, 50 g), eluting with agradient 0-10% MeOH/CH₂Cl₂ to give 4 as a white foam 393 mg (65.3%).

¹H NMR (300 MHz, CDCl₃) 1.4-1.8 (m,10H+H₂O); 2.1-2.3 (m,1H); 2.3-2.5(m,7H); 2.8(t,2H); 2.9 (s,3H); 3.1-3.45 (m, 4H); 3.45-3.9 (m,7H); 4.45(t,1H); 7.02 (s,1H); 7.1 (dd,1H); 7.2 (s,2H); 7.3 (d,1H); 7.45 (s,1H);8.2 (s,1H).

MS (ES⁺) m/z (M+H)⁺ 603.16

MS (ES⁻) m/z (M−H)⁻ 601.12

Example 5

STRUCTURE EXAMPLE

5.01Synthesis of this compound is described with reference to Scheme 7below.2N HCl (5 mL) was added to a stirred solution of R (200 mg, 0.331 mmol)in dioxane (5 mL) and the resulting solution left to stir for 72 hoursat room temperature. The reaction mixture was partitioned betweensaturated NaHCO₃ (100 mL) and EtOAc (4×50 mL). Combined organics weredried (MgSO₄), filtered and evaporated to a white foam. This was thenpurified by chromatography on SiO₂ (Varian, 10 g), eluting with agradient 0-10% MeOH/CH₂Cl₂ to give a white foam which was trituratedwith Et₂O (10 mL), filtered and dried under high vacuum to give 5 as awhite powder 99.4 mg (48%).

¹H NMR (300 MHz, DMSO-D₆+CD₃COOD)

0.50-0.80 (m,3H); 0.90-1.10 (m,3H); 1.45 (s,6H); 1.8-2.1 (m,1H); 2.2-2.4(m,7H); 2.70-3.00 (m,2H); 3.00-3.30 (m,4H); 3.30-3.65 (m,6H); 3.65-3.85(m,1H); 6.87 (d,1H); 6.95 (s,1H); 7.17(s, 2H); 7.20-7.35 (m,3H); 7.38(s,1H); 8.50 (d,2H).

MS (ES⁺) m/z (M+H)⁺ 622.51.

Synthesis of R (See Scheme 7)

4-Pyrrolidin-3-yl pyridine (1.00 g, 6.76 mmol) was added to a stirredsuspension of L (1.00 g, 1.80 mmol) [See Scheme 1] in IPA (5 ml) and themixture heated at reflux for 36 hours. The RM was concentrated in vacuoand the residues purified by chromatography on SiO₂ (Isolute, 50 g),eluting with a gradient 0-10% MeOH/CH₂Cl₂ to give R as a white foam 672mg (61%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.00-1.20 (m,3H); 1.60 (s,6H);1.80-2.00(m,1H); 2.10-2.30 (m,1H); 2.35 (s,6H); 2.80-3.00 (m,2H);3.10-3.50 (m, 8H); 3.60-3.80 (m,3H); 4.40 (m,1H); 6.97 (s,1H); 7.00-7.15(m,3H); 7.20 (s,2H); 7.28-7.36 (m,1H); 7.41 (s,1H); 8.22 (s,1H);8.48-8.60 (m,2H).

MS (ES⁺) m/z (M+H)⁺ 604.56

MS (ES⁻) m/z (M−H)⁻ 602.54

Following a procedure similar to that described in Example 5.01, thefollowing compound was prepared.

STRUCTURE EXAMPLE MS (ES)+

5.02 596.5 (M + H)+Preparation of Starting Materials (1)

Syntheses for starting materials B, C, D, E and F used in the aboveexamples are described with reference to Scheme 5 below.

2N NaOH (510 ml, 1.02 mol) was added to a stirred solution of A (48.5 g,205 mmol) in MeOH (550 ml) and the resulting mixture heated at refluxfor 2 hours. The RM was concentrated, acidified to pH 4 with 2N HCl andextracted with EtOAc (4×200 ml). The combined organics were washed withbrine (3×150 ml), dried (MgSO₄) filtered and evaporated to give B as acream powder 40.3 g (95%).

¹H NMR (300 MHz, CDCl₃) 1.66 (s,6H); 7.55 (m,2H); 8.20 (m,2H).

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-TetramethyluroniumHexafluoro-Phosphate (89.0 g, 290 mmol) was added portion wise to astirred, cooled (0° C.) solution of B (40.3 g, 192 mmol) in DMF (300 ml)and Diethylamine (300 ml). The resulting mixture was left to warn to RTand stir 70 hours. DMF was removed in vacuo and the residuesre-dissolved in EtOAc (500 ml), washed with water (3×200 ml), brine(2×200 ml), dried MgSO₄, filtered and evaporated.

The crudes were purified by flash chromatography on SiO₂ (600 g, Merck9385) eluting with 35% EtOAc/1-Hexane. Appropriate fractions werecombined and evaporated to give C as yellow crystalline solid 44.2 g(87%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.90 (m, 3H); 0.90-1.25 (m, 3H); 1.58(s,6H); 2.65-2.95 (m, 2H); 3.20-3.45 (m, 2H); 7.40 (m, 2H); 8.20 (m,2H).

LCMS (ES⁺) m/z (M+H)⁺ 265.48 (UV 254 nm 100%)

A solution of C (89.0 g, 338 mmol) in EtOH (2 L) was treated with 10%Pd/C (50% wet) (10.0 g) then stirred under H₂ (3 Bar) at RT for 3 hours.The RM was filtered through diatomaceous earth and evaporated to give Das a tan solid 65.5 g (83%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.90 (m,3H); 0.90-1.25 (m,3H); 1.48 (s,6H);2.80-3.10 (m,2H); 3.15-3.45 (m,2H); 3.45-3.75 (bs,2H); 6.60-6.70 (m,2H);6.90-7.05 (m, 2H).

MS (ES⁺) m/z (M+H)⁺ 235.61

N-Bromosuccinimide (18.24 g, 102.6 mmol) was added portion wise to astirred, cooled (0° C.) solution of D (24.0 g, 102.6 mmol) in CH₂Cl₂(250 ml) and the mixture stirred for 2 hours. The RM was evaporated, theresidues re-dissolved in EtOAc (200 ml), washed with saturated NaHCO₃(aq) (3×200 ml), water (2×200 ml), brine (200 ml), dried MgSO₄, filteredand evaporated. The crudes were purified by flash chromatography on SiO₂(500 g, Merck 9385) eluting with 5% MeOH/CH₂Cl₂. Appropriate fractionswere combined and evaporated to give E as a tan solid 30.4 g (94.7%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.90 (m,3H); 0.90-1.25 (m,3H); 1.48 (s,6H);2.80-3.10 (m,2H); 3.15-3.50 (m,2H); 3.80-4.20 (bs,2H); 6.72 (m,1H); 6.95(m,1H); 7.25 (m, 1H).

MS (ES⁺) m/z (M+H)⁺ 313.23, 315.26

A solution of E (15 g, 48 mmol) in conc HCl (48 ml) was cooled to −10°C. and to it was added drop wise a solution of NaNO₂ (3.97 g, 57.5 mmol)in water (24 ml) such that the internal temperature remained <−8° C. Theresulting solution was left to stir for 1 hr at this temperature beforeit was added drop wise to a solution of SnCl₂.2H₂O (53.0 g, 235 mmol) inconc HCl (36.5 ml) at −12° C. such that the internal temperatureremained <−10° C. The mixture was stirred for 2 hours at −10° C. thenallowed to warm to 10° C. before it was quenched into water (600 ml),neutralised with solid NaHCO₃, filtered and extracted with EtOAc (3×400ml). The organics were dried (MgSO₄), filtered and evaporated to ayellow oil. This was treated with 1 M HCl/Et₂O and dried to give the HClsalt of F as a free flowing white powder 14.7 g (84.4%)

¹H NMR (300 MHz, DMSO-D₆) 0.50-0.85 (m,3H); 0.85-1.10 (m,3H); 1.40(s,6H); 2.70-3.00 (m,2H); 3.00-3.40(m,2H); 7.00-7.10 (m,1H);7.10-7.20(m, 1H); 7.20-7.30 (m,1H).

LCMS (ES⁺) m/z (M+H)⁺ 328.3, 330.3 (UV 254 nm 95%)

Preparation of Starting Materials (2)

Syntheses for starting materials G, H, I, J and K used in the aboveexamples are described with reference to Scheme 6 below.

n-BuLi (1.6M in Hexanes) (100 ml, 160 mmol) was added drop wise to astirred, cooled (−78° C.) solution of 5-Bromoxylene (21.73 ml, 160 mmol)in THF (235 ml) and Et₂O (235 ml) such that the internal temperatureremained <−65° C. The resulting yellow suspension was allowed to stirfor 1.25 hours before it was added via a cannula to a stirred, cooled(−78° C.) solution of -Butyrolactone (14.7 ml, 192 mmol) in THF (180 ml)such that the internal temperature remained <−70° C. The mixture wasthen stirred at this temperature for a further 5 hours, quenched withsaturated NH₄Cl (200 ml) and extracted with Et₂O (3×100 ml). Thecombined organics were washed with brine (2×100 ml), dried (MgSO₄),filtered and concentrated to a yellow oil. This was then purified bychromatography on SiO₂ (Merck 9385) eluting with 45% EtOAc/1-Hexane togive G as a pale yellow oil 15.74 g (60%).

¹H NMR (300 MHz, DMSO-D₆) 1.70 (q,2H); 2.30 (s,6H); 2.98 (t,2H); 3.42(q,2H); 4.43 (t,1H); 7.22 (s,1H); 7.52(s, 2H).

Diethyl Azodicarboxylate (22.5 ml, 143 mmol) was added drop wise to astirred, cooled (−5° C.) solution of G (24.0 g, 124 mmol), Phthalimide(20.0 g, 136 mmol) and Triphenylphosphine (36.0 g, 136 mmol) in THF (450ml) such that the internal temperature remained <0° C. The RM wasstirred for 1 hr at this temperature, diluted with EtOAc (600 ml) andwashed with water (250 ml) and brine (250 ml). The organics were thendried (MgSO₄), filtered and concentrated to a yellow semi-solid. Thecrudes were purified by chromatography on SiO₂ (Merck 9385) eluting with25% EtOAc/1-Hexane to give H as a white powder 13.3 g (34%).

¹H NMR (300 MHz, DMSO-D₆) 1.80-2.00 (m,2H); 2.28 (s,6H); 3.03 (t,2H);3.62 (t,2H); 7.22 (s,1H); 7.47 (s,2H); 7.70 7.90 (m, 4H).

BF₃.Et₂O (30 ml) was added to a stirred solution of F (27.0 g, 74 mmol)and H (24.4 g, 77 mmol) in AcOH (450 ml) and the resulting mixtureheated at 90° C. for 48 hours. The RM was evaporated to dryness and theresidues treated with saturated NaHCO₃ (100 ml). The resulting solidswere collected by filtration, triturated with MeOH/CHCl₃ andre-filtered. The filtrates were concentrated to give I as an off-whitepowder 36 g (79%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.75(m,3H); 1.00-1.15 (m,3H); 1.54 (s,6H);2.25 (s,6H); 2.80-2.95 (m,2H); 3.24-3.40 (m,2H); 3.15-3.23 (m, 2H);3.80-3.90 (m,2H); 6.80 (s,1H); 7.06 (s,2H); 7.12 (s,1H); 7.45 (s,1H);7.55-7.70 (m,4H); 8.02 (s,1H).

LCMS (ES⁺) m/z (M+H)⁺ 613.9, 615.9 (UV 254 nm 100%)

A solution of I (42.0 g, 68 mmol) in MeOH (1000 ml) and Et₃N (10 ml) wastreated with 10% Pd/C (10.0 g) and stirred under H₂ (2 Bar) for 48hours. The catalyst was removed by filtration through diatomaceous earthand the filtrates evaporated. The residues were re-dissolved in EtOAc,washed with water, dried (MgSO₄), filtered and concentrated in vacuo togive J as a yellow foam 32.2 g (88%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.05-1.25 (m,3H); 1.60 (s,6H);2.30 (s,6H); 2.85-3.05 (m,2H); 3.20-3.50 (m,4H); 3.90-4.00 (m, 2H); 6.85(s,1H); 6.95-7.05 (m,1H); 7.12 (s,2H); 7.20-7.35 (m,1H+CHCl₃); 7.55-7.7(m,3H); 7.70-7.80 (m,2H); 8.00 (s,1H).

LCMS (ES⁺) m/z (M+H)⁺ 536.59 (UV 254 nm 100%)

LCMS (ES⁻) m/z (M−H)⁻ 534.58 (UV 254 nm 100%)

Hydrazine Hydrate (40 ml, 192 mmol) was added to a stirred solution of J(28 g, 52.3 mmol) in a mixture of MeOH (200 ml) and CH₂Cl₂ (200 ml) andstirred for 48 hours at RT. A further portion of Hydrazine Hydrate (40ml) was added and stirring continued for another 24 hours. The RM wasfiltered, washed with saturated NaHCO₃ (4×150 ml), brine (2×100 ml),dried (MgSO₄), filtered and evaporated. The crudes were purified byflash chromatography on SiO₂ (Merck 9385) eluting with EtOAc followed by10% MeOH/CH₂Cl₂ to give K as a pale yellow foam 17.1 g (80.6%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.05-1.25 (m,3H); 1.60 (s,6H);1.76 (s,2H+H₂O); 2.38 (s,6H); 2.80-3.12 (m,6H); 3.25-3.45 (m, 2H); 7.00(s,1H); 7.02-7.07(m,1H); 7.17 (s,2H); 7.25-7.35 (m,1H); 7.42 (s,1H);8.12 (s,1H).

LCMS (ES⁺) m/z (M+H)⁺ 406.56 (UV 254 nm 100%)

LCMS (ES⁻) m/z (M−H)⁻ 404.57 (UV 254 nm 100%)

Diphenyl cyanocarbonimidate (1.5 g, 6.3 mmol) was added to a stirredsolution of K (1.5 g, 3.7 mmol) in IPA and the mixture stirred 18 hoursat RT. The RM was concentrated in vacuo and the residues re-dissolved inEtOAc (150 ml). The organics were washed with saturated NaHCO₃ (3×70ml), brine (2×75 ml), dried (MgSO₄), filtered and evaporated. The crudeswere purified by flash chromatography on SiO₂ (Merck 9385) eluting witha gradient 0-5% MeOH/CH₂Cl₂ to give L as an off-white foam 1.9 g(95.4%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.00-1.20 (m,3H); 1.55(s,6H);2.35 (s,6H); 2.75-3.20 (m,2H); 3.10-3.45 (m, 4H); 3.60-3.75 (m,2H);6.30-6.45 (m,1H); 6.67-6.80 (m,2H); 7.00-7.50 (m,9H); 8.18 (s,1H).

MS (ES⁺) m/z (M+H)⁺ 550.36

MS (ES⁻) m/z (M−H)⁻ 548.30, 454.38

1,1 Bis(methylthio)-2-nitroethylene (515 mg, 3.1 mmol) was added to astirred solution of K (1.1 g, 2.72 mmol) in CH₃CN (70 ml) and heated atreflux for 18 hours. The RM was concentrated in-vacuo and the crudespurified by chromatography on SiO₂ (Merck 9385), eluting with 5%MeOH/CH₂Cl₂ to give M as a yellow foam 1.4 g (98%).

¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.05-1.25 (m,3H); 1.60 (s,6H);2.38(s,6H); 2.80-3.05 (m,2H); 3.25-3.50 (m, 4H); 3.68 (q,2H); 6.42(s,1H); 7.05 (s,1H); 7.06-7.15 (m,3H); 7.32 (d,1H); 7.45 (s,1H); 8.11(s,1H).

MS (ES⁺) m/z (M+H)⁺ 523.44

MS (ES⁻) m/z (M−H)⁻ 521.49

Therapeutic Uses

Compounds of formula I are provided as medicaments for antagonisinggonadotropin releasing hormone (GnRH) activity in a patient, eg, in menand/or women. To this end, a compound of formula I can be provided aspart of a pharmaceutical formulation which also includes apharmaceutically acceptable diluent or carrier (eg, water). Theformulation may be in the form of tablets, capsules, granules, powders,syrups, emulsions (eg, lipid emulsions), suppositories, ointments,creams, drops, suspensions (eg, aqueous or oily suspensions) orsolutions (eg, aqueous or oily solutions). If desired, the formulationmay include one or more additional substances independently selectedfrom stabilising agents, wetting agents, emulsifying agents, buffers,lactose, sialic acid, magnesium stearate, terra alba, sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butterand ethylene glycol.

The compound is preferably orally administered to a patient, but otherroutes of administration are possible, such as parenteral or rectaladministration. For intravenous, subcutaneous or intramuscularadministration, the patient may receive a daily dose of 0.1 mgkg⁻¹ to 30mgkg⁻¹ (preferably, 5 mgkg⁻¹ to 20 mgkg⁻¹) of the compound, the compoundbeing administered 1 to 4 times per day. The intravenous, subcutaneousand intramuscular dose may be given by means of a bolus injection.Alternatively, the intravenous dose may be given by continuous infusionover a period of time. Alternatively, the patient may receive a dailyoral dose which is approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day. Asuitable pharmaceutical formulation is one suitable for oraladministration in unit dosage form, for example as a tablet or capsule,which contains between 10 mg and 1 g (preferably, 100 mg and 1 g) of thecompound of the invention.

The following illustrate representative pharmaceutical dosage formscontaining a compound of the invention, or a pharmaceutically acceptablesalt or solvate thereof (hereafter referred to as “compound X”), for usein humans.

(a)

Tablet I mg/tablet Compound X. 100 Lactose Ph.Eur. 179 Croscarmellosesodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0(b)

Tablet II mg/tablet Compound X 50 Lactose Ph.Eur. 229 Croscarmellosesodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0(c)

Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur. 92 Croscarmellosesodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate 1.0(d)

Capsule mg/capsule Compound X 10 Lactose Ph.Eur. 389 Croscarmellosesodium 100 Magnesium stearate 1.(e)

Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueous solution to100%

Buffers, pharmaceutically acceptable co-solvents (eg, polyethyleneglycol, propylene glycol, glycerol or EtOH) or complexing agents such ashydroxy-propyl β cyclodextrin may be used to aid formulation.

One aspect of the invention relates to the use of compounds according tothe invention for reducing the secretion of LH and/or FSH by thepituitary gland of a patient. In this respect, the reduction may be byway of a reduction in biosynthesis of the LH and FSH and/or a reductionin the release of LH and FSH by the pituitary gland. Thus, compoundsaccording to the invention can be used for therapeutically treatingand/or preventing a sex hormone related condition in the patient. By“preventing” we mean reducing the patient's risk of contracting thecondition. By “treating” we mean eradicating the condition or reducingits severity in the patient. Examples of sex hormone related conditionsare: a sex hormone dependent cancer, benign prostatic hypertrophy, myomaof the uterus, endometriosis, polycystic ovarian disease, uterinefibroids, prostatauxe, myoma uteri, hirsutism and precocious puberty.Examples of sex hormone dependent cancers are: prostatic cancer, uterinecancer, breast cancer and pituitary gonadotrophe adenoma.

The compounds of the invention may be used in combination with otherdrugs and therapies used to treat/prevent sex-hormone relatedconditions.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

In the field of medical oncology examples of such combinations includecombinations with the following categories of therapeutic agent:

i) anti-angiogenic agents (for example linomide, inhibitors of integrinαvβ3 function, angiostatin, endostatin, razoxin, thalidomide) andincluding vascular endothelial growth factor (VEGF) receptor tyrosinekinase inhibitors (RTKIs) (for example those described in internationalpatent applications publication nos. WO-97/22596, WO-97/30035,WO-97/32856 and WO-98/13354, the entire disclosure of which documents isincorporated herein by reference);

ii) cytostatic agents such as anti-oestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (forexample megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrozole, vorazole, exemestane), anti-progestogens,anti-androgens (for example flutamide, nilutamide, bicalutamide,cyproterone acetate), inhibitors of testosterone 5α-dihydroreductase(for example finasteride), anti-invasion agents (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function) and inhibitors of growth factorfunction, (such growth factors include for example epidermal growthfactor (EGF), platelet derived growth factor and hepatocyte growthfactor such inhibitors include growth factor antibodies, growth factorreceptor antibodies, tyrosine kinase inhibitors and serine/threoninekinase inhibitors);

iii) biological response modifiers (for example interferon);

iv) antibodies (for example edrecolomab); and

v) anti-proliferative/anti-neoplastic drugs and combinations thereof, asused in medical oncology, such as anti-metabolites (for exampleanti-folates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); anti-tumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);anti-mitotic agents (for example vinca alkaloids like vincristine andtaxoids like taxol, taxotere); enzymes (for example asparaginase);thymidylate synthase inhibitors (for example raltitrexed); topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, irinotecan).

The compounds of the invention may also be used in combination withsurgery or radiotherapy.

Assays

The ability of compounds according to the invention to act asantagonists of GnRH can be determined using the following in vitroassays.

Binding Assay Using Rat Pituitary GnRH Receptor

The assay is performed as follows:—

-   1. Incubate crude plasma membranes prepared from rat pituitary    tissues in a Tris.HCl buffer (pH. 7.5, 50 mM) containing bovine    serum albumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and    the test compound. Incubation is at 4° C. for 90 minutes to 2 hours.-   2. Rapidly filter and repeatedly wash through a glass fibre filter.-   3. Determine the radioactivity of membrane bound radio-ligands using    a gamma counter.

From this data, the IC₅₀ of the test compound can be determined as theconcentration of the compound required to inhibit radio-ligand bindingto GnRH receptors by 50%. Compounds according to the present inventionhave activity at a concentration from 1 nM to 5 μM.

Binding Assay Using Human GnRH Receptor

Crude membranes prepared from CHO cells expressing human GnRH receptorsare sources for the GnRH receptor. The binding activity of compoundsaccording to the invention can be determined as an IC₅₀ which is thecompound concentration required to inhibit the specific binding of[¹²⁵I]buserelin to GnRH receptors by 50%. [¹²⁵I]Buserelin (a peptideGnRH analogue) is used here as a radiolabelled ligand of the receptor.

Assay to Determine Inhibition of LH Release

The LH release assay can be used to demonstrate antagonist activity ofcompounds, as demonstrated by a reduction in GnRH-induced LH release.

Preparation of Pituitary Glands

Pituitary glands obtained from rats are prepared as follows. Suitablerats are Wistar male rats (150-200 g) which have been maintained at aconstant temperature (eg, 25° C.) on a 12 hour light/12 hour dark cycle.The rats are sacrificed by decapitation before the pituitary glands areaseptically removed to tube containing Hank's Balanced Salt Solution(HBSS). The glands are further processed by:—

-   1. Centrifugation at 250×g for 5 minutes;-   2. Aspiration of the HBSS solution;-   3. Transfer of the glands to a petri dish before mincing with a    scalpel;-   4. Transfer of the minced tissue to a centrifuge tube by suspending    the tissue three successive times in 10 ml aliquots of HBSS    containing 0.2% collagenase and 0.2% hyaluronidase;-   5. Cell dispersion by gentle stirring of the tissue suspension while    the tube is kept in a water bath at 37° C.;-   6. Aspiration 20 to 30 times using a pipette, undigested pituitary    fragments being allowed to settle for 3 to 5 minutes;-   7. Aspiration of the suspended cells followed by centrifugation at    1200×g for 5 minutes;-   8. Re-suspension of the cells in culture medium of DMEM containing    0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1% non    essential amino acids, 1% glutamine and 0.1% gentamycin;-   9. Treatment of the undigested pituitary fragments 3 times with 30    ml aliquots of the collagenase and hyaluronidase;-   10. Pooling of the cell suspensions and dilution to a concentration    of 3×10⁵ cells/ml;-   11. Placing of 1.0 ml of this suspension in each of a 24 well tray,    with the cells being maintained in a humidified 5% CO₂/95% air    atmosphere at 37° C. for 3 to 4 days    Testing of Compounds

The test compound is dissolved in DMSO to a final concentration of 0.5%in the incubation medium.

1.5 hours prior to the assay, the cells are washed three times with DMEMcontaining 0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1%non essential amino acids (100×), 1% glutamine (100×), 1%penicillin/streptomycin (10,000 units of each per ml) and 25 mM HEPES atpH 7.4. Immediately prior to the assay, the cells are again washed twicein this medium.

Following this, 1 ml of fresh medium containing the test compound and 2nM GnRH is added to two wells. For other test compounds (where it isdesired to test more than one compound), these are added to otherrespective duplicate wells. Incubation is then carried out at 37° C. forthree hours.

Following incubation, each well is analysed by removing the medium fromthe well and centrifuging the medium at 2000×g for 15 minutes to removeany cellular material. The supernatant is removed and assayed for LHcontent using a double antibody radio-immuno assay. Comparison with asuitable control (no test compound) is used to determine whether thetest compound reduces LH release. Compounds according to the presentinvention have activity at a concentration from 1 nM to 5 μM.

1. A compound of formula I or a salt, pro-drug or solvate thereof

wherein for A, either:— (i) A represents hydrogen or optionallysubstituted C₁ to C₈ alkyl; or (ii) the structure N—A(—R⁴) represents anoptionally substituted 3- to 8-membered heterocyclic ring optionallycontaining from 1 to 3 further heteroatoms independently selected fromO, N and S; B represents a direct bond or optionally substituted C₁ toC₅ alkylene; C represents a mono- or bi-cyclic aromatic ring structureoptionally having at least one substituent selected from CN, NR⁵R⁶, anoptionally substituted C₁ to C₈ alkyl, optionally substituted C₁ to C₈alkoxy or halo; D represents hydrogen; optionally substituted C₁ to C₈alkyl; or (CH₂)_(b)—R^(a), wherein R^(a) is C₃ to C₈ cycloalkyl and brepresents zero or an integer from 1 to 6; E is selected from anoptionally substituted 3- to 8-membered heterocyclic ring containingfrom 1 to 4 heteroatoms independently selected from O, N and S; or agroup of formula II; III; IV; V; VI, VII or VIII

wherein het represents an optionally substituted 3- to 8-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from O, N and S; for X and Y, either:— (iii) X represents N andY represents CN; hydrogen or —CONR^(b)R^(c) where R^(b) and R^(c) areindependently selected from hydrogen and C₁ to C₈ alkyl; (iiia) Xrepresents CH and Y represents NO₂; or (iv) X—Y represents O; For R¹ andR², either:— (v) R¹ and R² are independently selected from hydrogen andoptionally substituted C₁ to C₈ alkyl; or (vi) R¹ and R² togetherrepresent carbonyl; or (vii)

represents an optionally substituted 3- to 8-membered heterocyclic ringcontaining from 1 to 3 further heteroatoms independently selected fromO, N and S, and R² meets the definition in option (v); R³ meets thedefinition in option (vii) or represents hydrogen or optionallysubstituted C₁ to C₈ alkyl; R⁴ meets the definition in option (ii), orwhen A meets the definition in option (i) R⁴ represents hydrogen oroptionally substituted C₁ to C₈ alkyl; R⁵ and R⁶ are independentlyselected from hydrogen; optionally substituted C₁ to C₈ alkyl andoptionally substituted aryl; for R⁷ and R^(7a), either:— (viii) R⁷ andR^(7a) are independently selected from hydrogen or optionallysubstituted C₁ to C₈ alkyl; or (ix)

represents an optionally substituted 3 to 7-membered cycloalkyl ring;for R⁸ and R⁹, either:— (x) R⁸ is selected from hydrogen; optionallysubstituted C₁ to C₈ alkyl; optionally substituted aryl; —R^(d)—Ar,where R^(d) represents C₁ to C₈ alkylene and Ar represents optionallysubstituted aryl; and an optionally substituted 3- to 8-memberedheterocyclic ring optionally containing from 1 to 3 further heteroatomsindependently selected from O, N and S; and R⁹ is selected fromhydrogen; optionally substituted C₁ to C₈ alkyl and optionallysubstituted aryl; (xi) wherein E represents a group of formula II orIII, then the group NR⁸(—R⁹) represents an optionally substituted 3- to8-membered heterocyclic ring optionally containing from 1 to 3 furtherheteroatoms independently selected from O, N and S; or (xii) wherein Erepresents structure VI,

represents an optionally substituted 3- to 8-membered heterocyclic ringoptionally containing from 1 to 4 heteroatoms independently selectedfrom O, N and S; with the proviso that: when A is C₁ to C₈ alkyl or thestructure N—A(—R⁴) represents an optionally-substituted 3- to 8-memberedheterocyclic ring containing from 1 to 3 heteroatoms independentlyselected from O, N and S; X represents N and Y represents CN orhydrogen, X represents CH and Y represents NO₂ or X—Y represents O; thenthe optional substituents on A are not selected from optionallysubstituted phenyl or an optionally-substituted 3- to 8-memberedheterocyclic ring.
 2. The compound of claim 1, wherein —N—A(—R⁴) meetsthe definition in option (ii) and is selected from anoptionally-substituted group of formula IX, X or Xi,


3. The compound of claim 2, wherein —N—A(—R⁴) is selected from XII orXIII

wherein R¹² represents C₁ to C₈ alkyl; —(CH₂)_(c)NR^(e)R^(f), where c iszero or an integer from 1 to 4, and R^(e) and R^(f) independentlyrepresent hydrogen or C₁ to C₈ alkyl; hydroxy; halo; CN; C₁ to C₈alkoxy; or CF₃.
 4. The compound of claim 1, wherein A and R⁴ eachrepresent hydrogen.
 5. The compound of claim 1, wherein, E represents(a) structure II of the sub-formula

wherein Me represents methyl; (b) structure II, wherein

represents cyclopropyl or cyclobutyl; or (c) structure VIII wherein R⁷and R^(7a) each represent methyl.
 6. The compound of claim 1, wherein Crepresents

wherein Me represents methyl.
 7. The compound of claim 1, wherein R¹ andR² each represent hydrogen and B represents C₁ alkylene.
 8. The compoundof claim 1, wherein the compound is selected from a compound of formulaXXI to XXXI

or salt, pro-drug or solvate thereof.
 9. A pharmaceutical formulationcomprising a compound, or salt, pro-drug or solvate thereof, accordingto claim 1 and a pharmaceutically acceptable diluent or carrier.
 10. Aprocess of producing a compound, or salt, pro-drug or solvate thereof,according to claim 1, wherein the process comprises a reaction selectedfrom any one of (a) to (e):— (a) Reaction of a compound of formula XXXIIas follows

(b) Cleavage of the CN group of a compound of formula XXXIII in thepresence of acid to produce a compound of formula XXXIV

(c) Reaction of a compound of formula XXXV as follows

(d) Reaction of a compound of formula XXXVII as follows

(e) Reaction of a compound of formula XXXIX as follows

and thereafter, optionally: i) converting a compound of the formula Iinto another compound of the formula I; ii) removing any protectinggroups; iii) forming a salt, pro-drug or solvate.